Adenoviruses form the basis of some of the most innovative and potentially powerful disease-fighting tools. One such tool is gene therapy, in which an exogenous nucleotide sequence provided to a cell. This approach holds great potential in treating not only cancer, but many other diseases as well, including cystic fibrosis, anemia, hemophilia, diabetes, Hungtington's disease, AIDS, abnormally high serum cholesterol levels, certain immune deficiencies, and many forms of cancer. Gene therapy generally relies upon a delivery vehicle, such as a viral vector in order to provide the exogenous sequence to a cell. Recombinant adenovirus has shown some therapeutic efficacy against these diseases. For reviews, see Kim et al. (1996) Mol. Med. Today 12:519-527 and Smith et al. (1996) Gene Therapy 3:496-502. Adenoviruses that replicate selectively in target cells are being developed as therapeutic agents for treatment of cancer.
In an alternate approach applicable to cancer treatment, specific attenuated replication-competent viral vectors have been developed for which selective replication in cancer cells preferentially destroys those cells. Various cell-specific replication-competent adenovirus constructs, which preferentially replicate in (and thus destroy) certain cell types, are described in, for example, WO 95/19434, WO 96/17053, WO 98/39464, WO 98/39465, WO 98/39467, WO 98/39466, WO 99/06576, WO 99/25860, WO 00/15820, WO 00/46355, WO 02/067861, WO 02/06862, U.S. Patent application publication US20010053352 and U.S. Pat. Nos. 5,698,443, 5,871,726, 5,998,205, and 6,432,700. Replication-competent adenovirus vectors have been designed to selectively replicate in tumor cells.
Although replication-competent adenoviruses are able to achieve selective targeting and amplification for the treatment of local and disseminated cancers, there remains a need for improvement in both the adenovirus vectors themselves and methods for their use dependent upon the type of cancer under treatment.